Recent evidence suggests that pentraxins interact with Fc receptors raising the possiblity of cross interaction between the complement and the Fc receptor mediated pathways. We are investigating the interaction between SAP/CRP and Fc receptors and determine the structure of their complex. We have recently determined the crystal structure of human SAP in complex with FcRIIa. The 1:1 receptor-SAP recognition is predominantly mediated through the interactions of the ridge helix from two separate SAP protomers with the D1 and D2 domains of the Fc receptor. The complex structure between human SAP and FcRIIa reveals a diagonally bound receptor on each SAP pentamer. Mutational analysis suggests a conserved receptor recognition among pentraxins. The shared binding site for SAP and IgG results in their competition to FcR binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. These results establish the role of innate pentraxins in the FcgR pathway, and have novel therapeutic implications for autoimmune diseases.Unexpectedly, the SAP binding site on FcRIIa overlaps partially with the IgG binding site on the receptor. The solution-based binding experiments confirmed that SAP and CRP competed against IgG for the binding to FcRs. Solutuion binding experiments showed that pentraxins recognize various FcRs and activate FcR-mediated phagocytosis and cytokine secretion. Moreover, soluble SAP and CRP inhibited significantly the immune complex-mediated phagocytosis, indicating a regulatory function for this family of plasma proteins. The result highlights the importance of pentraxins in interfacing between the innate and humoral immunities and suggests new therapeutic applications for pentraxins in autoimmune diseases. We recently identified the major IgA receptor, FcRI as a ligand for pentraxins. We conclude through competitive binding and mutational analysis that CRP binds to a distinct site on FcRI from that of IgA, and that the recognition involves the effector face of CRP in a region overlapping with its C1q and FcR binding site. Furthermore, CRP crosslinking of FcRI resulted in ERK phosphorylation, degranulation and cytokine production in FcRI transfected RBL cells. In neutrophils, CRP binding induced FcRI surface expression and TNF- secretion, and CRP-opsonized bacteria triggered phagocytosis. The impact of this work is two folds. First, the discovery that pentraxins activate FcRI reveals a novel function for pentraxins in inflammation. It implicates a potential pentraxin-mediated synergistic activation of various Fc receptors in neutrophil and macrophage-mediated inflammatory responses. This is particular so since neutrophils and macrophages are the first responders of infection and inflammation. Second, our finding also highlights the innate aspect of antibody receptors that are mediators of humoral immunity. As pentraxins, such as CRP, are acute phase proteins whose expressions are upregulated during infections, we are investigating the potential role of CRP in Fc receptor activations during parasitic and viral infections. Serum Amyloid A (SAA) represents an evolutionarily conserved family of inflammatory acute phase proteins. It is also a major constituent of secondary amyloidosis. To understand its function and structural transition to amyloid, we determined the first structure of human SAA1.1 in two crystal forms, representing a prototypic member of the family. Native SAA1.1 exists as a hexamer with subunits displaying a unique four-helix bundle fold stabilized by its long C-terminal tail. The structural-based mutational studies revealed two positive charge clusters, near the center and apex of the hexamer, are involved in SAA association with heparin. The binding of high density lipoprotein (HDL) involves only the apex region of SAA and can be inhibited by heparin. Peptide amyloid formation assays identified the N-terminal helix 1 and helix 3 as amyloidogenic peptides of SAA1.1. Both peptides are secluded in the hexameric structure of SAA1.1, suggesting the native SAA as non-pathogenic. Further, dissociation of the SAA hexamer appears insufficient to initiate amyloidogenic transition, and proteolytic cleavage or removal of the C-terminal tail of SAA resulted in formation of various sized structural aggregates containing 5 nm regular repeating protofibril-like units. The combined structural and functional studies provide mechanistic insights to the pathogenic contribution of glycosaminoglycan in SAA1.1-mediated AA amyloid formation. To elucidate the molecular mechanism of its high affinity IgG binding, we determined the crystal structure of the extracellular domains of human Fc&#947;RI in complex with the Fc domain of human IgG1. Fc&#947;RI binds to the Fc in the same mode as the low affinity Fc&#947;RII and Fc&#947;RIII receptors, and shares the conserved contacts to the lower hinge region of Fc. Unique to the high affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG-loop to enable a charged KHR motif to interact with proximal carbohydrate units on the Fc glycans. Both the length and charge of the Fc&#947;RI FG-loop are well conserved among Fc&#947;RI homologs. Ala and Glu mutations of the FG-loop KHR residues showed significant contributions from His 174 and Arg 175 to antibody binding, and the loss of the FG-loop glycan contacting residues resulted in a 20-30 fold decrease in Fc&#947;RI affinity to IgG1 and IgG3, and a 12 fold decrese to IgG4 affinity. The binding of the mutant Fc&#947;RI receptors to IgG1 is comparable to that of wild type Fc&#947;RI to deglycosylated IgG1, demonstrating the involvement of the receptor FG-loop in glycan recognition. These results highlight the unique contribution of glycan recognition to Fc&#947;RI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan-mimics to target Fc&#61543;RI for certain autoimmune diseases.